LKB1 Regulates Pancreatic β Cell Size, Polarity, and Function

Zvi Granot, Avital Swisa, Judith Magenheim, Miri Stolovich-Rain, Wakako Fujimoto, Elisabetta Manduchi, Takashi Miki, Jochen K. Lennerz, Christian J. Stoeckert, Oded Meyuhas, Susumu Seino, M. Alan Permutt, Helen Piwnica-Worms, Nabeel Bardeesy, Yuval Dor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

136 Scopus citations


Pancreatic β cells, organized in the islets of Langerhans, sense glucose and secrete appropriate amounts of insulin. We have studied the roles of LKB1, a conserved kinase implicated in the control of cell polarity and energy metabolism, in adult β cells. LKB1-deficient β cells show a dramatic increase in insulin secretion in vivo. Histologically, LKB1-deficient β cells have striking alterations in the localization of the nucleus and cilia relative to blood vessels, suggesting a shift from hepatocyte-like to columnar polarity. Additionally, LKB1 deficiency causes a 65% increase in β cell volume. We show that distinct targets of LKB1 mediate these effects. LKB1 controls β cell size, but not polarity, via the mTOR pathway. Conversely, the precise position of the β cell nucleus, but not cell size, is controlled by the LKB1 target Par1b. Insulin secretion and content are restricted by LKB1, at least in part, via AMPK. These results expose a molecular mechanism, orchestrated by LKB1, for the coordinated maintenance of β cell size, form, and function.

Original languageAmerican English
Pages (from-to)296-308
Number of pages13
JournalCell Metabolism
Issue number4
StatePublished - 7 Oct 2009

Bibliographical note

Funding Information:
We are grateful to Rachel Hertz and Jacob Bar-Tana for providing advice and generously sharing unpublished reagents. We thank Cris Welling for technical assistance; Morris Birnbaum for providing RIP-AKT mice; Bangyan Stiles for providing slides of PTEN mutant mice; Ittai Ben-Porath, Hadas Masuri, and Rotem Karni for assistance with viral infections; and Chris Wright for the gift of anti pdx1 antibodies. Y. Dor was supported by grants from JDRF, NIH (BCBC), ISF, ICRF (Barbara Goodman PC-RCDA), the Sixth Framework Programme of the European Union, and the JDRF Center for β Cell Therapy in Diabetes. This work was supported in part by an NIH grant (R37 DK16746, to M.A. Permutt) and the Core Research for Evolutional Science and Technology (CREST) to S. Seino. The Washington University DRTC (NIH P60 DK20579) is acknowledged for assistance from the Immunoassay Core. C. Stoeckert and E. Manduchi were supported by JDRF and NIH (BCBC).




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